Alzheimer?s disease (AD) is the most common cause of cognitive impairment in older adults and affects over 5 million people in the US alone. Individuals who carry the apolipoprotein E-?4 (APOE4) gene are at heightened risk for developing late onset AD while individuals with the presenilin 1 (PSEN1) gene mutation will develop autosomal-dominant AD. Project 2 of the proposed P01 ?Vascular Contributions to Dementia and Genetic Risk Factors for Alzheimer?s Disease? will provide critical advances towards discovering how changes in brain connectivity, structure and function relate to neurovascular integrity and ultimately confer cognitive impairment in AD genetic risk groups. Across 5 sites, Project 2 will recruit 722 participants, including 294 APOE4 carriers and 340 non-carriers, and 44 PSEN1 mutation carriers and 44 non-carriers, followed longitudinally to evaluate changes in brain structure and function. Participants with NCI or early MCI will receive our imaging protocol every 2 years: 1) multi-shell DTI for white matter network connectivity; 2) resting fMRI for functional network connectivity; 3) structural MRI for gray matter shape, volume; and 4) DCE-MRI, ASL perfusion (from Project 1); in addition to Uniform Data Sets (UDS) cognitive tests. 150 participants (50 APOE4 carriers, 100 non-carriers) will also complete an amyloid PET scan to examine the effect of amyloid deposition on brain function and structure. We will address aims directed at assessing differences in structural and functional connectivity, examining the temporal association between brain connectivity changes over time, understanding how brain connectivity predicts future cognitive decline, and evaluating how blood-brain barrier integrity impacts brain connectivity. The relationship between structural connectivity, functional connectivity, and neurovascular integrity has not been explored. Using advanced neuroimaging methodology, this project will apply a hypothesis-driven approach to understand how brain structure and function change in individuals with high genetic risk for AD, and the impact of neurovascular integrity on these changes.